Neurochemistry International[JOURNAL]
Sun
200 papers
Deferoxamine prevents BBB disruption, neuroinflammation and apoptotic changes in early hours of ischemic reperfusion injury.
Ugale R, Vatte S, Girdhar P … +1 more , Anandani D
Neurochem Int · 2025 Sep · PMID 40517956 · Publisher ↗
BACKGROUND: Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under inve...
BACKGROUND: Iron contributes to brain damage in ischemia/reperfusion injury (I/R). Deferoxamine (DFX), an iron chelator, offers neuroprotective action in I/R animal models. However, its underlying mechanism is under investigation. This study aims to investigate effect of DFX on I/R damage led by BBB disruption, neuroinflammation, and apoptosis. METHODS: In adult male Wistar rats, cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Rats were treated with vehicle or DFX at 100, 200, and 300 mg/kg doses intraperitoneally (i.p.) at time intervals 1, 2, and 3 h of I/R injury. The neuroprotective effect of DFX was observed using histological staining and behavioural assessment after 24 h of I/R injury. Blood-brain barrier (BBB) integrity was evaluated by Evans blue staining & MMP9 expression. Anti-inflammatory effect of DFX was observed using immunohistochemical analysis whereas, anti-apoptotic effects via mRNA expressions of CREB, caspase-3, BDNF and Bcl-2. RESULTS: DFX (300 mg/kg) at 1 h of I/R injury ameliorates cerebral infarction, neurological deficits, and beam walk score. Histologically, Hoechst, hematoxylin and eosin (H & E), and cresyl violet stainings showed reduced neuronal death in DFX treated rats. It mitigates BBB disruption as observed with Evans blue staining. Additionally, DFX reduced MMP-9 expression indicative of reduced BBB disruption and improved inflammatory changes (CD86 and CD206). Besides, it inhibits mRNA expression of cleaved caspase-3 and improved expression of BDNF and Bcl-2. CONCLUSIONS: Our findings, demonstrate that DFX prevents I/R brain damage in early hour (1 h) of I/R injury by reducing BBB disruption, inflammation, and apoptosis. DFX may exhibit potential to act as adjuvant in management of acute ischemic stroke.
Epitranscriptomic shifts in M6A RNA methylation influencing transcriptional dynamics in the prefrontal cortex of chronic restraint stress rats.
Funahashi Y, Roy B, Prall K … +1 more , Dwivedi Y
Neurochem Int · 2025 Sep · PMID 40517955 · Full text
Chronic restraint stress (CRS) is a widely used model for investigating stress-induced molecular and neuronal changes. In this study, we examined transcriptome-wide m6A methylation in the prefrontal cortex of CRS rats to...
Chronic restraint stress (CRS) is a widely used model for investigating stress-induced molecular and neuronal changes. In this study, we examined transcriptome-wide m6A methylation in the prefrontal cortex of CRS rats to understand the molecular impact of stress. Elevated plasma corticosterone levels confirmed the physiological stress response in CRS rats. MeRIP-seq analysis identified 21,669 differentially methylated transcripts, with a predominant hypermethylation pattern (4,301 transcripts) compared to a smaller subset of hypomethylated transcripts (79). Chromosomal distribution revealed widespread hypermethylation across multiple chromosomes, with notable peaks on chromosomes 1, 3, and 10. Gene expression profiling indicated differential regulation of 1,424 genes, with 847 upregulated and 577 downregulated in CRS rats. Integration of m6A methylation and gene expression data revealed an inverse correlation, where hypermethylated transcripts were downregulated, suggesting a role for m6A in transcript stability and turnover. Functional analysis of hypermethylated transcripts highlighted enrichment in key neuronal processes, including synaptic plasticity, neurotransmitter signaling, and chromatin remodeling. Additionally, the 3'UTR of coding transcripts exhibited enriched m6A methylation marks, suggesting a regulatory role in mRNA stability and translation efficiency. RNA level expression analysis revealed significant downregulation of key m6A methylation-related enzymes (METTL3, METTL14, and ALKBH5), further supporting m6A dysregulation under CRS. Pathway analysis underscored the involvement of differentially methylated transcripts in RNA metabolism, chromatin remodeling, and neurobiological pathways linked to stress-related psychiatric disorders. Altogether, the study provides insight into the epitranscriptomic mechanisms underlying stress responses and their implications in neuropsychiatric disorders such as major depression.
DNA methylation and hydroxymethylation dynamics in the aging brain and its impact on ischemic stroke.
Arruri V, Joshi P, Vemuganti R
Neurochem Int · 2025 Sep · PMID 40513956 · Full text
DNA methylation and hydroxymethylation patterns at the 5th carbon of cytosine (5mC and 5hmC) in CpG dinucleotides tightly regulate gene transcription in normal physiology, aging, and associated diseases, including ischem...
DNA methylation and hydroxymethylation patterns at the 5th carbon of cytosine (5mC and 5hmC) in CpG dinucleotides tightly regulate gene transcription in normal physiology, aging, and associated diseases, including ischemic stroke. Resilience to ischemic brain injury depends on the interplay of diverse neural and non-neural cell types, whose gene expression and identity are predominantly regulated by brain-enriched epigenetic mechanisms, particularly the dynamics of 5mC and 5hmC in response to changing transcriptional demands under ischemic stress. In this review, we discussed the role of 5mC and 5hmC in aging and the pathophysiology of stroke. Given the high degree of inter-individual variability in stroke studies and its multifactorial etiology, we emphasize the need for personalized, temporally controlled, epigenome-based therapies to improve stroke outcomes.
Neurochemical in vivo microdialysis and postmortem tissue analysis of amygdala endocannabinoid levels after MAGL- and FAAH-inhibition in rodents.
Heins MS, Ferger MD, Voehringer P … +2 more , Cremers TIFH, Ferger B
Neurochem Int · 2025 Sep · PMID 40494414 · Publisher ↗
This study is the first to investigate the target modulation of the MAGL inhibitor elcubragistat (ABX-1431; Lu-AG06466) and the FAAH inhibitor JNJ-42165279 in the amygdala, a brain region involved in stress-induced psych...
This study is the first to investigate the target modulation of the MAGL inhibitor elcubragistat (ABX-1431; Lu-AG06466) and the FAAH inhibitor JNJ-42165279 in the amygdala, a brain region involved in stress-induced psychiatric disorders. We aimed to assess dynamic changes in the endocannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide (AEA) following pharmacological inhibition of MAGL and FAAH, enzymes regulating their metabolism. Freely moving rats received oral doses of elcubragistat or JNJ-42165279. Microdialysis probes in the basolateral amygdala and nucleus accumbens measured extracellular 2-AG and AEA levels over 240 min using LC-MS/MS. A supplementary mouse study analyzed postmortem endocannabinoid levels in the basolateral amygdala. MAGL inhibition by elcubragistat selectively increased extracellular and tissue 2-AG levels in the basolateral amygdala in a dose-related manner without affecting AEA. Conversely, FAAH inhibition by JNJ-42165279 selectively elevated AEA levels without altering 2-AG. Highest endocannabinoid concentration in basolateral amygdala tissue was between 2 and 4 h after MAGL or FAAH inhibition. In vivo microdialysis is a sensitive method to study target modulation of both MAGL and FAAH inhibitors in the amygdala of freely moving rats. The results of the microdialysis study are in general agreement with postmortem tissue analysis of both 2-AG and AEA and suitable to support the preclinical drug discovery process in concert with disease related animal models.
Epigenetic regulation of immune cells in central nervous system: from steady state to pathology.
Zhao L, Schepp CL, Iskandar M … +2 more , Tao Y, Dey M
Neurochem Int · 2025 Sep · PMID 40482971 · Publisher ↗
The central nervous system (CNS) and immune system interact on a regular basis in homeostasis and in pathology. The immune system's response to CNS pathology is intricately regulated by epigenetic regulation of various i...
The central nervous system (CNS) and immune system interact on a regular basis in homeostasis and in pathology. The immune system's response to CNS pathology is intricately regulated by epigenetic regulation of various immune cells that allows these cells to perform diverse and complex functions in a context-dependent manner. Epigenetics refers to modulation of gene expression that is influenced by environmental factors and doesn't depend on alteration of DNA sequence. Epigenetic regulation, such as DNA methylation, histone modification and non-coding RNA, lies at the heart of immune cell biology, integrating intrinsic transcriptional programs with extrinsic signals to dictate different immune cell behaviors. Dysregulation of epigenetic mechanisms largely affects the immune response in various diseases. Understanding epigenetic regulation provides a promising approach to manipulate immune cells behaviors in various disease contexts, thus offering therapeutic benefit window. Here, we review recent findings regarding immune cell behavior and epigenetic regulation in the context of CNS physiology and pathology. We also discuss how epigenetic mechanism contributes to cancer immunotherapy response, as well as ways to utilize combination therapy using epigenetic modifiers and personalized medicine approach to manipulate immune cell function to improve immunotherapy outcomes.
Gastrin-releasing peptide in the paraventricular nucleus exerts hypertensive effects in preeclampsia.
Wang X, Ali MA, Liu X … +9 more , Zeng M, Zeng Z, Yuan M, Issotina Zibrila A, Liu S, Ping N, Kang Y, Li X, Liu J
Neurochem Int · 2025 Sep · PMID 40460928 · Publisher ↗
BACKGROUND: Preeclampsia (PE) is a pregnancy complication associated with hypertension, whose central mechanism remains unclear. Gastrin-releasing peptide (GRP) is involved in the regulation of central blood pressure, ho...
BACKGROUND: Preeclampsia (PE) is a pregnancy complication associated with hypertension, whose central mechanism remains unclear. Gastrin-releasing peptide (GRP) is involved in the regulation of central blood pressure, however, whether GRP and its receptor, GRPR, in the paraventricular nucleus of the hypothalamus (PVN) are involved in blood pressure regulation in PE is unknown. METHODS: In this study, we initially assessed GRP/GRPR expression levels and their cellular distribution within the PVN of a PE rat model with reduced uterine perfusion pressure (RUPP). We investigated the effect of five-day antagonism of GRPR with ICI-216140 (1 mM/side/day, PVN microinjection) on PVN activity in this model. On gestational day 19 (GD19), the mean arterial pressure (MAP) was recorded, and samples were collected for analysis. We also investigated the effect of losartan on RUPP-induced changes in MAP and GRP/GRPR expression in the PVN. RESULTS: RUPP rats exhibited increased MAP, and GRP and GRPR expression in the PVN. GRPR antagonism with ICI-216140 attenuated RUPP intervention-increased MAP and expression of oxidative stress markers including NOX2, NOX4, and reactive oxygen species, NF-κB, and tyrosine hydroxylase in the PVN. While ICI-216140 did not affect the expression of angiotensin II receptor type 1 (AT1R), the blockade of AT1R with losartan decreased MAP 2and GRP expression in RUPP rats. CONCLUSIONS: Our findings suggest that GRP expression in the PVN mediates placental ischemia-induced hypertension and may depend on AT1R activity, which provides new pharmacological avenues for animal models of PE.
A multiscale atlas of Oprm1-expressing neurons in the central nervous system: Brain-wide distribution, circuit functions, and translational therapeutic implications.
Zhang Z, Hu S, Geng S … +7 more , Xu T, Liu X, Lei Z, Sun C, Sun H, Xie W, Mu M
Neurochem Int · 2025 Sep · PMID 40447056 · Publisher ↗
The mu-opioid receptor (MOR), encoded by the Oprm1 gene, critically modulates diverse physiological processes including pain perception, reward behaviors, emotional regulation, and autonomic control. The genetic complexi...
The mu-opioid receptor (MOR), encoded by the Oprm1 gene, critically modulates diverse physiological processes including pain perception, reward behaviors, emotional regulation, and autonomic control. The genetic complexity and region-specific distribution of Oprm1-expressing neurons underpin both the therapeutic actions and adverse effects of opioid drugs. In this comprehensive review, we systematically construct a multiscale atlas of Oprm1-expressing neurons throughout the central nervous system (CNS) by integrating genetic labeling, neuroanatomical mapping, functional circuit analyses, and translational perspectives. We highlight three interconnected aspects: (1) brain-wide regional distribution patterns, revealing enriched Oprm1 expression across sensory, limbic, and autonomic circuits; (2) functional heterogeneity of Oprm1-expressing neurons, elucidating their distinct roles in nociception, reward processing, emotional and neuroendocrine regulation, with a particular emphasis on sex differences and adaptive plasticity under stress; (3) translational opportunities for therapeutic interventions, focusing on innovative strategies such as circuit-specific opioid modulation and biased agonism, designed to optimize analgesic benefits while minimizing addiction liability and respiratory depression. Furthermore, we critically examine existing challenges and knowledge gaps, including receptor trafficking mechanisms, dynamic changes in Oprm1 expression under conditions such as chronic opioid exposure or stress, interspecies differences, and network-level opioid signaling dynamics. This integrative framework provides essential insights into MOR neurobiology, facilitating the development of next-generation opioid therapeutics that leverage precise modulation of neural circuits and molecular pharmacological advancements. The translational implications of understanding these aspects are emphasized throughout this review, aiming to bridge basic neurobiological findings with clinical applications.
Bioactive ROS-responsive nanotherapeutics attenuate intermittent hypoxia-induced cognitive impairment via NRF2/KEAP1/HO-1 signaling.
Huang Y, Xie H, Liu L … +3 more , Zhao H, Li B, Zhang F
Neurochem Int · 2025 Sep · PMID 40436344 · Publisher ↗
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal apoptosis, ultimately leading to progressive cognitive impairment. This study investigated...
Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (IH), which induces oxidative stress and neuronal apoptosis, ultimately leading to progressive cognitive impairment. This study investigated the neuroprotective potential of a reactive oxygen species (ROS)-responsive nanotherapeutic, namely TPCD nanoparticles (TPCD NP), synthesized through the conjugation of Tempol and phenylboronic acid pinacol ester to β-cyclodextrin, in both in vivo and in vitro models. In rats, intravenous administration of TPCD NP improved memory performance as assessed by the Morris water maze test, and preserved hippocampal neuronal morphology. TPCD NP significantly reduced intracellular ROS content and malondialdehyde (MDA) levels while restoring antioxidant capacity, including superoxide dismutase (SOD) and glutathione (GSH). Apoptosis was attenuated, as evidenced by the downregulation of Bax and cleaved caspase-3, and the upregulation of Bcl-2 expression. Mechanistically, TPCD NP enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), suppressed Kelch-like ECH-associated protein 1 (KEAP1), and increased heme oxygenase-1 (HO-1) expression. The protective effects were abolished by ML385, a selective NRF2 inhibitor, confirming the essential role of NRF2 activation in mediating the antioxidant and anti-apoptotic effects of TPCD NP. In conclusion, TPCD NP attenuates oxidative stress and apoptosis induced by IH in the hippocampus by activating the NRF2/KEAP1/HO-1 pathway. These findings highlight TPCD NP as a promising therapeutic strategy for OSA-associated neurodegeneration.
Activation or blockade of prelimbic 5-HT receptors improves working memory in hemiparkinsonian rats.
Yang J, Chen L, Li X … +8 more , Guo Y, Hu H, Li F, Wang T, Wang Y, Yao L, Zhang L, Liu J
Neurochem Int · 2025 Sep · PMID 40414564 · Publisher ↗
Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine (5-HT) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation...
Working memory deficits commonly occur in Parkinson's disease. 5-hydroxytryptamine (5-HT) receptors are widely distributed in the prelimbic cortex (PrL) and involved in cognition. Here we tested the effects of activation and blockade of PrL 5-HT receptors on working memories by T-maze rewarded alternation and Morris water maze tests in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle. The lesion induced working memory deficits, decreased dopamine levels in the limbic-related brain regions, changed normalized δ, high θ, α, β, low and high γ power of the PrL, and upregulated expression of PrL 5-HT receptor. Intra-PrL injection of 5-HT receptor agonist BIMU8 or antagonist GR113808 did not impact working memories in sham rats, but improved working memory deficits in the lesioned rats. Intra-PrL injection of BIMU8 or GR113808 had no effect on monoamine levels in the limbic-related brain regions or normalized low and high γ power of the PrL in sham rats. However, in the lesioned rats, intra-PrL injection of BIMU8 significantly increased dopamine and 5-HT levels in the medial prefrontal cortex, amygdala and dorsal hippocampus, while intra-PrL injection of GR113808 significantly increased dopamine levels in these brain regions and increased normalized low and high γ power of the PrL. These results suggest that 6-OHDA lesion in rats induces working memory deficits, while activation or blockade of PrL 5-HT receptors improves the deficits in the lesioned rats, which possibly due to the changes of monoamine levels in the limbic-related brain regions and network activity of neurons in the PrL.
Intermittent theta burst stimulation is superior to 10 Hz-repetitive transcranial magnetic stimulation in promoting episodic-like memory in healthy male rats by enhancing low γ oscillation and glutamate neuronal activities of the anterior cingulate cortex.
Wang Y, Hui Y, Wang L … +6 more , Qiao H, Wu X, Bai Y, Sun Q, Zhang Q, Li L
Neurochem Int · 2025 Sep · PMID 40398749 · Publisher ↗
Intermittent theta-burst stimulation (iTBS) and high-frequency repetitive transcranial magnetic stimulation (rTMS) produce beneficial after-effects on memory performance. The two modalities have modulatory after-effects...
Intermittent theta-burst stimulation (iTBS) and high-frequency repetitive transcranial magnetic stimulation (rTMS) produce beneficial after-effects on memory performance. The two modalities have modulatory after-effects on the prefrontal neuronal oscillations and neurotransmitters, which are critically involved in episodic memory processing. However, whether iTBS exerts better cognitive effects than high-frequency rTMS through modulating neuronal oscillations and neurotransmitter levels in the prefrontal cortex has not been determined. Thus, iTBS and 10 Hz-rTMS modalities were applied to healthy male rats respectively, and behavior tests, electrophysiological experiments and microdialysis and neurochemistry were performed. We found that iTBS and 10 Hz-rTMS promoted episodic memory in healthy male rats, and iTBS exerted better cognitive effects than 10 Hz-rTMS. Intriguingly, iTBS induced greater effects than 10 Hz-rTMS in enhancing low γ oscillation in the anterior cingulate cortex (ACC) which is a subregion of the prefrontal cortex. Further, compared to sham stimuli, iTBS suppressed δ oscillation and enhanced θ oscillation, while 10 Hz-rTMS did not, suggesting that iTBS induces higher cortical excitability in the ACC than 10 Hz-rTMS. This is supported by a higher increase in glutamate neuronal activities in the ACC following iTBS than 10 Hz-rTMS. Finally, we found that iTBS and 10 Hz-rTMS decreased extracellular gamma-aminobutyric acid levels and increased extracellular glutamate levels in the ACC, thus leading to the activation of ACC glutamate neurons after the two modalities. These findings suggest that iTBS produces better cognitive effects in healthy male rats, which may be attributed to enhanced low γ oscillation and activated glutamatergic neurons in the ACC.
Impact of NLRP6 inflammasome on neuroinflammation in temporal lobe epilepsy.
Guo Y, Song J, Chen Y … +2 more , Lü Y, Yu W
Neurochem Int · 2025 Sep · PMID 40398748 · Publisher ↗
Epilepsy is one of the most common and severe chronic brain diseases, affecting up to 70 million people worldwide. Neuroinflammation plays a central role in the progression of the disease. The Nod-Like Receptor Protein 6...
Epilepsy is one of the most common and severe chronic brain diseases, affecting up to 70 million people worldwide. Neuroinflammation plays a central role in the progression of the disease. The Nod-Like Receptor Protein 6 (NLRP6) inflammasome assembles with apoptosis-associated speck-like protein (ASC) to cleave pro-caspase-1 into caspase-1, thus forming the NLRP6 inflammasome. This process promotes the maturation and release of downstream interleukins (IL)-18 and IL-1β, exacerbating pathological processes in various diseases. In this study, we demonstrated significantly enhanced NLRP6 expression in the cortex and hippocampus of epileptic mice, suggesting a role for the inflammasome in epilepsy. Immunofluorescence staining further revealed that NLRP6 was predominantly expressed in hippocampal neurons of these mice. Additionally, knockdown of NLRP6 reduced susceptibility to epilepsy, alleviated post-seizure neuronal damage, and decreased levels of pro-inflammatory cytokines, including IL-18, IL-1β, and IL-6. Conversely, NLRP6 overexpression produced opposite effects, which were effectively reversed by treatment with the caspase-1 inhibitor VX765. To the best of our knowledge, this is the first study to demonstrate a link between NLRP6 and the activation of the caspase-1/IL-1β/IL-18 signaling pathway in a kainic acid (KA)-induced epilepsy mouse model. Administration of VX765 alleviated pathological alterations and exerted neuroprotective effects. These findings suggest that NLRP6 plays a critical role in the initiation and progression of epilepsy.
Overexpression of TAFA4 in the dorsal root ganglion ameliorates neuropathic pain in male rats through promoting macrophage M2-Skewing.
Ai Z, Li H, Xu S … +5 more , Cai C, Wang X, Guan Y, Guo R, Wang Y
Neurochem Int · 2025 Jul · PMID 40381955 · Publisher ↗
Neuro-immune interactions between macrophages and primary sensory neurons have been implicated in nerve injury and associated pain. This study aims to explore the function of the TAFA4 as a crucial neuroimmune regulator...
Neuro-immune interactions between macrophages and primary sensory neurons have been implicated in nerve injury and associated pain. This study aims to explore the function of the TAFA4 as a crucial neuroimmune regulator in modulating macrophage states within the context of neuropathic pain. To elucidate the role of TAFA4 in dorsal root ganglia (DRG) following a chronic constriction injury (CCI) model in male rats, immunofluorescent staining, western blot, flow cytometry analysis and enzyme-linked immunosorbent assay were performed. Microinjection of self-complementary adeno-associated virus expressing TAFA4 mRNA into the L4 and L5 DRGs was conducted to overexpress TAFA4 in the DRGs. Following peripheral nerve injury, we observed a downregulation of TAFA4 in ipsilateral DRG neurons. Restoring this downregulation effectively alleviated the mechanical and thermal nociceptive hypersensitivity by inhibiting pro-inflammatory mediators while promoting the secretion of anti-inflammatory cytokines on day 14 post-CCI. Notably, scAAV-TAFA4 microinjection also facilitated the polarization of macrophages in the DRGs towards the M2 phenotype. Mechanistically, TAFA4 modulates the functions of macrophages in a lipoprotein receptor-related protein 1-dependent manner. Our findings revealed the role of TAFA4 in shifting macrophages in favor of an anti-inflammatory phenotype and enhancing interleukin 10 concentrations in the DRG, suggesting it is a potential analgesic target for alleviating neuropathic pain.
Proteostasis and autophagy disruption by the aging-related VGVAPG hexapeptide - preliminary insights into a potential novel elastin-induced neurodegeneration pathway in an in vitro human cellular neuron model.
Skóra B, Szychowski KA
Neurochem Int · 2025 Jul · PMID 40348194 · Publisher ↗
The hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is the most readily released product of elastin degradation, a process closely associated with aging. Recent studies have demonstrated the ability of this peptide to upreg...
The hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is the most readily released product of elastin degradation, a process closely associated with aging. Recent studies have demonstrated the ability of this peptide to upregulate Sirtuin 2 (SIRT2) mRNA and protein expression. The correlation between HRD1 ligase (Synoviolin 1) and the degradation of SIRT2 has been previously reported in the literature. This study aimed to explore the impact of VGVAPG-induced interaction between HRD1 and SIRT2 and its effects on autophagy in differentiated SH-SY5Y cells in vitro (a simplified model of neurons). The results revealed that VGVAPG decreases HRD1 mRNA and protein expression while correlating with SIRT2 overexpression. Further analysis showed reduced SEL1L protein levels and an increase in p97/VCP protein expression. Additionally, enhanced phosphorylation of IRE1α indicated induction of ER stress in the tested cell model without affecting mTOR. Decreased proteasome activity and accumulation of ubiquitin were also noted. This phenomenon triggered VGVAPG-induced autophagy, as evidenced by increased expression of autophagy-related proteins ATG16L1, ATG5, ATG18, and FIP200. However, autophagy was suppressed probably as a result of VGVAPG-induced phosphorylation of ERK1/2. These findings demonstrate that the aging-related hexapeptide VGVAPG downregulates the function of the SEL1L-HRD1 complex, leading to SIRT2 accumulation and subsequent ER stress due to ERAD and UPS. This cascade, in turn, activates autophagy as an alternative clearance pathway aimed at restoring proteostasis; however, the process becomes dysregulated, leading to persistent ER stress. This dual effect may have significant implications in neurobiology, given the well-established correlation between autophagy impairment and aging-related neurodegenerative disorders.
Eslicarbazepine, a third-generation anti-seizure medication, inhibits I but stimulates I.
Hung TY, Wu SN, Huang CW
Neurochem Int · 2025 Jul · PMID 40345391 · Publisher ↗
Eslicarbazepine (ESL) is a new antiseizure medication used to treat focal epilepsy. It is not entirely clear how ESL affects the magnitude and gating kinetics of membrane ionic currents, although a few reports have demon...
Eslicarbazepine (ESL) is a new antiseizure medication used to treat focal epilepsy. It is not entirely clear how ESL affects the magnitude and gating kinetics of membrane ionic currents, although a few reports have demonstrated its ability to suppress voltage-gated Na currents (I). With the aid of patch clamp technology, docking prediction, and simulation modeling, this study was conducted to investigate the potential modifications through which ESL may induce on ionic currents, including I, M-type K current (I), and erg-mediated K current (I), in hippocampal neurons. ESL distinctly inhibited transient I (I) and late I (I), demonstrating greater potency against I. ESL shifted the steady-state inactivation curve of I leftward without altering its steepness or activation curve. Additionally, ESL attenuated the tefluthrin-induced enhancement of voltage-dependent hysteresis (Hys) of persistent I (I). ESL increased I in a concentration-dependent manner, shifting its steady-state activation curve toward more depolarized potentials and enhancing Hys(V) strength. It also increased the activity and mean open time of I without affecting single-channel conductance. Minimal changes were observed in the magnitude of I. Predicted docking analysis revealed that ESL binds to the hNa1.7 channel via hydrogen bonds and hydrophobic contacts. Simulation modeling using hippocampal CA1 pyramidal neurons demonstrated that ESL's inhibition of I and stimulation of I, along with changes in their Hys(V), modulate neuronal action potential firing. Overall, these findings highlight ESL's dual effects on I and I, revealing mechanisms that likely contribute to its efficacy in treatment of epilepsy.
Therapeutic potential of cell-permeable PEP-1-Srxn1 in mitigating oxidative and ischemic damage in the hippocampus.
Hahn KR, Kwon HJ, Moon SM … +4 more , Kim W, Hwang IK, Kim DW, Yoo DY
Neurochem Int · 2025 Jul · PMID 40345390 · Publisher ↗
In the present study, we validated the neuroprotective effects of sulfiredoxin 1 (Srxn1) against oxidative damage in HT22 cells and ischemic damage in gerbil hippocampus. To efficiently deliver Srxn1 protein into cells o...
In the present study, we validated the neuroprotective effects of sulfiredoxin 1 (Srxn1) against oxidative damage in HT22 cells and ischemic damage in gerbil hippocampus. To efficiently deliver Srxn1 protein into cells or the hippocampus, a PEP-1-Srxn1 fusion protein was synthesized, and efficient delivery was visualized in HT22 mouse hippocampal neuronal cells. PEP-1-Srxn1 was delivered to HT22 cells in a concentration- and incubation time-dependent manner and showed significantly higher levels at 36 h after incubation for 1 h. Morphologically, the delivered protein was localized in the cytoplasm of HT22 cells. In addition, PEP-1-Srxn1 treatment significantly ameliorated formation of reactive oxygen species, DNA fragmentation, and cell death in HT22 cells induced by treatment with 100 μM HO. In gerbils, PEP-1-Srxn1 treatment significantly alleviated transient ischemia-induced forebrain hyperactivity 1 d after ischemia and memory deficits 4 d after ischemia. Neuroprotective effects were confirmed by morphological analysis of the hippocampal CA1 region 4 or 10 d after ischemia. Treatment with PEP-1-Srxn1 significantly ameliorated the formation of reactive oxygen species and lipid peroxidation in the hippocampus during the early stages (3-12 h) of ischemia. In addition, treatment with PEP-1-Srxn1 alleviated the ischemia-induced reduction of glutathione levels in the hippocampus. PEP-1-Srxn1 also decreased ischemia-induced microglial activation and pro-inflammatory cytokine release in the hippocampus. These results suggest that PEP-1-Srxn1 is a potential therapeutic agent for reducing neuronal damage induced by oxidative or ischemic damage.
Sulforaphane prevents cognitive decline and mitochondrial failure induced by hippocampal expression of caspase-3 cleaved tau.
Villavicencio-Tejo F, Olesen MA, Ampuero E … +1 more , Quintanilla RA
Neurochem Int · 2025 Jul · PMID 40339911 · Publisher ↗
Caspase-3 cleaved tau (truncated tau) is a pathological modification in tau protein that contributes to neurofibrillary tangle formation (NFTs) and neurodegeneration in AD. Our previous studies indicate that truncated ta...
Caspase-3 cleaved tau (truncated tau) is a pathological modification in tau protein that contributes to neurofibrillary tangle formation (NFTs) and neurodegeneration in AD. Our previous studies indicate that truncated tau affects mitochondrial health, synaptic plasticity, and cognitive performance. Therefore, we studied the effects of sulforaphane (SFN), a natural compound activator of the NRF2 antioxidant pathway present in vegetables and sprouts, on neurodegeneration and cognitive decline induced by truncated tau expression in vivo. We induced a 2-month hippocampal expression of GFP, full-length (AAV-Syn-GFP-T4) and truncated tau (AAV-Syn-GFP-T4C3) using a stereotaxic injection of adeno-associated-virus-9 (AAV9) linked to GFP and a synapsin neuronal promoter in tau (-/-) mice. Hippocampal tau-expressing mice were treated with SFN, and their cognitive performance (NOR, NOL, and Barnes maze tests) and hippocampal mitochondrial function were analyzed. Interestingly, hippocampal truncated tau expression significantly affected cognitive and memory abilities, accompanied by increased ROS and severe mitochondrial dysfunction (depolarization, ATP loss, dynamics de-regulation). Notably, the treatment with SFN (50 mg/kg/day, i.p., two weeks) prevented cognitive impairment and reduced mitochondrial bioenergetics and dynamics defects induced by hippocampal truncated tau expression. These findings suggest a potential role of SFN in ameliorating cognitive loss and mitochondrial impairment promoted by tau pathology in neurological disorders (NDs).
The effect of Fibulin-5 on early brain injury after subarachnoid hemorrhage in mice.
Suzuki Y, Nampei M, Kawakita F … +3 more , Oinaka H, Nakajima H, Suzuki H
Neurochem Int · 2025 Jul · PMID 40339910 · Publisher ↗
Early brain injury (EBI) is an important cause that determines outcomes after aneurysmal subarachnoid hemorrhage (SAH). Our recent clinical study reported that a high concentration of plasma fibulin-5 (FBLN5), one of mat...
Early brain injury (EBI) is an important cause that determines outcomes after aneurysmal subarachnoid hemorrhage (SAH). Our recent clinical study reported that a high concentration of plasma fibulin-5 (FBLN5), one of matricellular proteins, was associated with poor outcomes after SAH. The aim of this study was to investigate whether and how FBLN5 was associated with EBI during an acute phase of SAH in mice. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or four dosages (0.001, 0.01, 0.1, and 1 μg) of short or long recombinant FBLN5 (rFBLN5) were randomly administrated by an intracerebroventricular injection. Neurobehavioral test, measurements of brain water content, immunohistochemical staining, and Western blotting were performed to evaluate EBI 24 h after SAH. Short rFBLN5 had no significant effects on EBI, but administration of long rFBLN5 containing an arginine-glycine-aspartic acid motif improved neurobehavior functions depending on the dosages, without affecting brain edema. Administration of long rFBLN5 also reduced cleaved caspase-3-dependent neuronal apoptosis, associated with the inhibition of post-SAH upregulation of transforming growth factor-β1, but no significant changes in the expression level of Smad 2/3, mitogen-activated protein kinases, and another matricellular protein tenascin-C. Although further research is required to clarify the detailed mechanism, this study demonstrated for the first time that FBLN5 played a protective role against neuronal apoptosis in an acute phase of experimental SAH.
Effects of maternal depression and antidepressant treatment on neurotransmitters, brain regions, and mitochondrial function in rat dams.
Maková M, Kašparová S, Bačiak L … +5 more , Gogola D, Sumbalová Z, Brucknerová I, Bukatová S, Dubovický M
Neurochem Int · 2025 Jul · PMID 40319913 · Publisher ↗
Increasing evidence suggests that mothers experience stress before or during pregnancy, which can significantly impact their GABAergic system and lead to amygdala hyperactivity. While animal models are expected to reflec...
Increasing evidence suggests that mothers experience stress before or during pregnancy, which can significantly impact their GABAergic system and lead to amygdala hyperactivity. While animal models are expected to reflect the above findings in humans, the current knowledge on the effects of chronic unpredictable mild stress (CUMS) in rat dams remains insufficient. Therefore, the objective of this study was to investigate the structural and neurochemical alterations in the dorsal hippocampus, specifically gamma-aminobutyric acid (GABA) and glutamate (Glu) relative to total creatine (tCr), induced by the CUMS and the effects of antidepressant mirtazapine (MIR) treatment. Magnetic resonance imaging and proton localized magnetic resonance spectroscopy were used in rat dams at two time points to assess the reversibility of these alterations. Eight weeks post-CUMS, chronic stress induced significant alterations in hippocampal metabolism and structural changes, including lower GABA/tCr concentrations and an increased amygdala volume compared to controls. In stressed dams treated with MIR, no changes in GABA levels or amygdala volume were observed. Fourteen weeks post-CUMS, no significant changes in hippocampal neurochemistry were confirmed, while amygdala changes persisted in stressed dams. Moreover, significant time-dependent changes were observed in the amygdala and hypothalamus in the control group with MIR. Interestingly, high-resolution respirometry was performed to assess brain mitochondrial function, revealing only changes in this group. Based on these findings, we confirmed the reversibility of metabolite. Furthermore, MIR has demonstrated potential in regulating neurotransmitter levels and protecting amygdala volume after stress; however, further research is needed to fully understand its therapeutic effects.
Truncation mutation of CHMP2B disrupts late endosome function but reduces TDP-43 aggregation through HSP70 upregulation.
Iguchi Y, Takahashi Y, Li J … +7 more , Amakusa Y, Kawakami Y, Yoshimura T, Chikuchi R, Iida M, Yokoi S, Katsuno M
Neurochem Int · 2025 Jul · PMID 40316175 · Publisher ↗
TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantia...
TAR DNA-binding protein 43 (TDP-43)-positive cytoplasmic aggregation is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). This aggregation contributes substantially to the neurodegeneration of ALS and FTLD. The endosome, a key component of membrane trafficking in eukaryotic cells and is involved in the autophagy-lysosome pathway. Endosome-related genes such as CHMP2B, Alsin, and TMEM106B, are either causative or act as genetic modifiers in ALS and FTLD. However, the association between endosomal functions and TDP-43 aggregations remain poorly understood. The C-terminal truncation mutation CHMP2B, which causes frontotemporal dementia associated with chromosome 3 (FTD3), disrupts late endosome (LE)-lysosomes fusion. Nevertheless, FTD3 does not induce TDP-43 pathology. In this study, we showed that CHMP2B mutation-induced LE dysfunction promotes TDP-43 aggregate degradation through enhanced recruitment to juxtanuclear quality control compartments. Transcriptomic analysis revealed that CHMP2B overexpression upregulates HSP70 expression. New insights into the connection between CMHP2B and HSP70 as well as the role of HSP70-mediated membrane trafficking in TDP-43 aggregation, offer a valuable understanding of the disease mechanism of ALS and FTLD.
Corrigendum to "Supplementation with g-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD" [Neurochem. Int. 144 (2021) 104931].
Liu Y, Chen Z, Li B … +6 more , Yao H, Zarka M, Welch J, Sachdev P, Bridge W, Braidy N
Neurochem Int · 2025 Jul · PMID 40312198 · Publisher ↗
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